Recombinant COL6 α2 as a Self-Organization Factor That Triggers Orderly Nerve Regeneration Without Guidance Cues.

Zhou Fang,Jian-Long Zou

doi:10.3389/fncel.2021.816781

Abstract

Collagen VI (COL6) in the microenvironment was recently identified as an extracellular signal that bears the function of promoting orderly axon bundle formation. However, the large molecular weight of COL6 (≈2,000 kDa) limits its production and clinical application. It remains unclear whether the smaller subunit α chains of COL6 can exert axon bundling and ordering effects independently. Herein, based on a dorsal root ganglion (DRG) ex vivo model, the contributions of three main COL6 α chains on orderly nerve bundle formation were analyzed, and COL6 α2 showed the largest contribution weight. A recombinant COL6 α2 chain was produced and demonstrated to promote the formation of orderly axon bundles through the NCAM1-mediated pathway. The addition of COL6 α2 in conventional hydrogel triggered orderly nerve regeneration in a rat sciatic nerve defect model. Immunogenicity assessment showed weaker immunogenicity of COL6 α2 compared to that of the COL6 complex. These findings suggest that recombinant COL6 α2 is a promising material for orderly nerve regeneration.

Highlights

Peripheral nerve injury is a common disease for which there exist a large number of nerve repair strategies, including end-to-end neurorrhaphy, nerve grafting, gene therapy, and electrical stimulation
Encouraged by the results of these studies, here, we present a comparative study on the function and immunogenicity of recombinant COL6 α chains, which aimed to determine the independent effect of COL6 subunit chains on axonal self-organization with potential application in peripheral nerve injury
The formation of orderly axon bundles was inhibited by antibodies against COL6 α1 and COL6 α2; the antibody to COL6 α3 exhibited a relatively weak inhibitory effect on the fasciculation and alignment of axons (Figure 1A)

Summary

Introduction

Peripheral nerve injury is a common disease for which there exist a large number of nerve repair strategies, including end-to-end neurorrhaphy, nerve grafting, gene therapy, and electrical stimulation. The introduction of extrinsic guidance signals in nerve grafts is an effective strategy for orderly axon regeneration (Krick et al, 2011; Liu et al, 2018) These approaches require the anisotropic distribution of guidance signals, such as gradient-distributed biochemical cues or well-aligned physical cues, within small nerve grafts (Handarmin et al, 2011; Oh et al, 2018; Hsu et al, 2019). Their axon-ordering effects are severely limited by the development of manufacturing techniques

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Results

Conclusion